HK1046277B - Benzamide formulation with histone deacetylase inhibitor activity - Google Patents
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
There are provided pharmaceutical formulations with improved oral absorptivity and injections that contain, as active ingredients, high concentrations of benzamide derivatives and their pharmaceutically acceptable salts, which are useful as histone deacetylase inhibitors.A pharmaceutical solution is prepared by dissolving a benzamide derivative or a pharmaceutically acceptable salt thereof in an organic solvent and/or acidic liquid, and a pharmaceutical formulation is prepared by adding a surfactant, an acidic substance and/or a polyethylene glycol.The present invention has enabled dissolution of benzamide derivatives or their pharmaceutically acceptable salts at high concentrations, to prepare practical injections and oral liquid formulations and improve absorptivity with oral administration.
Description
Technical Field
The present invention relates to a pharmaceutical preparation having increased solubility and containing a benzamide derivative or a pharmaceutically acceptable salt thereof, which is useful as a medicament, particularly an anticancer agent. In particular, the present invention relates to pharmaceutical preparations containing a high concentration of active ingredient and having improved oral absorbability, which can also be used as injections.
Background
The benzamide derivatives and pharmaceutically acceptable salts thereof used in the present invention have histone deacetylase inhibitory action and are useful as therapeutic and/or ameliorating agents for diseases associated with cell growth, as effect enhancers for gene therapy, and as immunosuppressive agents. They have a particularly strong action as anticancer agents and are effective against hematopoietic tissue tumors and solid tumors (Japanese unexamined patent publication (Kokai) No. Hei-10-152462).
However, although the benzamide derivative used in the present invention has a very satisfactory absorbability when orally administered to mice and rats, some cases of low absorbability are found in dogs. Even when the formulation is prepared using common additives such as lactose, corn starch, carboxymethyl cellulose, light silicic anhydride, magnesium aluminum silicate, magnesium stearate and titanium dioxide, some cases of low absorbability for oral administration are found. Therefore, it has been considered that it is difficult to achieve a stable blood concentration only with an orally administered formulation containing a benzamide derivative or a salt thereof as an active ingredient.
There have also been attempts to dissolve a benzamide derivative or a pharmaceutically acceptable salt thereof in water, a phosphate buffer solution or the like to prepare a liquid drug or an injection solution, but their low solubility makes it impossible to obtain a formulation of a sufficient concentration.
Therefore, an injection solution containing a benzamide derivative or a salt thereof as an active ingredient must have a very large volume due to poor solubility of the active ingredient and thus it is difficult to provide it as a drug.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a formulation having increased solubility and improved oral absorbability of benzamide derivatives and pharmaceutically acceptable salts thereof useful as histone deacetylase inhibitors, and to provide an injection containing an active ingredient at a high concentration.
The present inventors have conducted extensive studies to improve solubility and absorbability by adding various additives to benzamide derivatives and pharmaceutically acceptable salts thereof in order to overcome the above problems, and as a result, have found that the object can be achieved by using certain types of additives, and thus have completed the present invention.
In other words, the invention provides
[1] A pharmaceutical preparation comprising a benzamide derivative represented by the formula (1):
wherein A represents a structure represented by any one of the following formulae (2):
or a pharmaceutically acceptable salt thereof, and one or more selected from the group consisting of a surfactant, an acidic substance, an organic solvent and polyethylene glycol;
[2] the pharmaceutical preparation according to [1], further comprising water;
[3] the pharmaceutical preparation according to [1] or [2], wherein the benzamide derivative is represented by the formula (3):
[4] the pharmaceutical formulation according to any one of [1] to [3], wherein the surfactant is one or two selected from the group consisting of an anionic surfactant and a nonionic surfactant;
[5] the pharmaceutical preparation according to any one of [1] to [4], wherein the acidic substance is one or more selected from the group consisting of inorganic acids, carboxylic acids, sulfonic acids, acidic polysaccharides, acidic amino acids, and salts of amino acids and inorganic acids;
[6] the pharmaceutical preparation according to any one of [1] to [5], wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, propylene glycol, glycerin, propylene carbonate and dimethylacetamide;
[7] the pharmaceutical preparation according to any one of [1] to [6], wherein the molecular weight of the polyethylene glycol is 200-20,000;
[8] the pharmaceutical formulation according to any one of [4] to [7], wherein the anionic surfactant is sodium lauryl sulfate;
[9] the pharmaceutical preparation according to any one of [4] to [8], wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester or a sugar ester;
[10] the pharmaceutical preparation according to [9], wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80;
[11] the pharmaceutical preparation according to [9], wherein the sugar ester is a sucrose ester of a fatty acid;
[12] the pharmaceutical preparation according to any one of [5] to [11], wherein the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid;
[13] the pharmaceutical preparation according to any one of [5] to [11], wherein the carboxylic acid is citric acid, fumaric acid, adipic acid, tartaric acid, malic acid or acetic acid;
[14] the pharmaceutical preparation according to any one of [5] to [11], wherein the sulfonic acid is aminoethanesulfonic acid;
[15] the pharmaceutical preparation according to any one of [5] to [11], wherein the acidic polysaccharide is alginic acid;
[16] the pharmaceutical preparation according to any one of [5] to [11], wherein the acidic amino acid is aspartic acid or glutamic acid;
[17] the pharmaceutical preparation according to any one of [5] to [11], wherein the salt of the amino acid and the inorganic acid is glycine hydrochloride, aspartic acid hydrochloride or glutamate hydrochloride.
Brief Description of Drawings
FIG. 1 illustrates the series of changes in plasma concentration of the formulations obtained in examples 2 to 4 and comparative example 1 when they are administered orally to fasted male beagle dogs (beagle) with a 20ml mouth.
Modes for carrying out the invention
The invention will now be explained in more detail. Formulations are generally prepared by incorporating one or more additives into the active ingredient.
Benzamide derivatives represented by the formula (1) of the present invention which are used as active ingredients of the preparations are exemplified in Table 1 and these compounds can be produced by, for example, the method described in Japanese unexamined patent publication Hei-10-152462.
TABLE 1
Compound 1
Compound 2
Compound 3
The surfactant used in the present invention is not particularly limited, and includes anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, and the like; sodium lauryl sulfate, polysorbate 80, sucrose esters of fatty acids, and the like are preferably used alone or in combination.
The acidic substance used in the present invention includes inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethanesulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of amino acids and inorganic acids such as glycine hydrochloride, aspartic acid hydrochloride, and glutamic acid hydrochloride.
One or more acidic substances may be used in the present invention.
These acidic substances may be formulated with the active ingredient together with a surfactant, an organic solvent, polyethylene glycol and/or the like, but they may also be used as a solution in water.
Organic solvents useful in the present invention include methanol, ethanol, propylene glycol, glycerol, dimethylformamide, and propylene carbonate, and one or more of them may be used, optionally in the form of a solution in water.
The polyethylene glycol used in the present invention is not particularly limited in terms of its molecular weight, but preferably its molecular weight is 200-. One or more types may be optionally used, optionally in the form of a solution in water.
The liquid-encapsulated soft capsule and liquid-encapsulated hard capsule and the like of the present invention can be prepared by dissolving an appropriate amount of a benzamide derivative or a pharmaceutically acceptable salt thereof in a solvent
(i) A liquid containing one or more selected from the group consisting of an organic solvent, polyethylene glycol and a surfactant;
(ii) a liquid containing water and one or more selected from the group consisting of an organic solvent, polyethylene glycol and a surfactant;
(iii) a liquid comprising one or more acidic substances, water and one or more selected from the group consisting of an organic solvent, polyethylene glycol and a surfactant; or
(iv) Liquid containing one or more acidic substances and water, and making into liquid-encapsulated soft capsules and liquid-encapsulated hard capsules, etc. according to a method commonly used by those skilled in the art.
Organic solvents used for preparing soft and hard capsules and the like include methanol, ethanol, propylene glycol, glycerin, dimethylformamide and propylene carbonate; polyethylene glycols used in the preparation of soft and hard capsules and the like include polyethylene glycols having a molecular weight of 200-600; surfactants used in the preparation of soft and hard capsules and the like include polysorbate 80; and acidic substances used for the preparation of soft and hard capsules and the like include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethanesulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of amino acids and inorganic acids such as glycine hydrochloride, aspartic acid hydrochloride, and glutamic acid hydrochloride.
According to the present invention, solid preparations such as powders, granules, tablets, pills and capsules can be prepared by: one or more substances selected from the following are added to the active ingredient according to methods commonly used by those skilled in the art: surfactants such as sodium lauryl sulfate and sucrose esters of fatty acids; polyethylene glycols such as polyethylene glycol 4000 and polyethylene glycol 6000; including inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethanesulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and acidic substances including salts of amino acids and inorganic acids such as glycine hydrochloride, aspartic acid hydrochloride, and glutamic acid hydrochloride, and also excipients, binders, disintegrants, lubricants, coating agents, and the like for formulation are used.
Excipients useful in the present invention include D-mannitol, lactose, sucrose, corn starch, crystalline cellulose, and the like. Binders useful in the present invention include hydroxypropyl cellulose, polyvinyl pyrrolidone, gelatin, glycerin, water, and the like.
Disintegrants for use in the invention include carboxymethylcellulose (carmellose), carboxymethylcellulose calcium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, partially pregelatinized starch, and the like. Lubricants useful in the present invention include magnesium stearate, calcium stearate, and the like.
Coating agents useful in the present invention include hydroxypropyl methylcellulose, methacrylic acid copolymers, hydroxypropyl methylcellulose phthalate, and the like.
The tablets may be those which are coated, if desired, with customary coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets or film-coated tablets. Further, the tablet may be a bilayer or multilayer tablet having separate layers of the active ingredient, the acidic substance, the surfactant and the like.
The injection solution of the present invention can be prepared by dissolving an appropriate amount of the benzamide derivative or a pharmaceutically acceptable salt thereof in a solvent
(i) A liquid containing one or more selected from the group consisting of an organic solvent, polyethylene glycol and a surfactant;
(ii) a liquid containing water and one or more selected from the group consisting of an organic solvent, polyethylene glycol and a surfactant;
(iii) a liquid comprising one or more acidic substances, water and one or more selected from the group consisting of an organic solvent, polyethylene glycol and a surfactant; or
(iv) A liquid comprising one or more acidic substances and water, and prepared by making an injection according to a method commonly used by those skilled in the art.
Organic solvents used for preparing injections include methanol, ethanol, propylene glycol, glycerol, dimethylformamide and propylene carbonate; polyethylene glycols used in the preparation of injections include polyethylene glycols having a molecular weight of 200-600; surfactants used in the preparation of injections include polysorbate 80; and acidic substances used for preparing injections include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; carboxylic acids such as acetic acid, lactic acid, fumaric acid, tartaric acid, succinic acid, citric acid, oxalic acid, malonic acid, maleic acid, dl-malic acid, stearic acid and adipic acid; sulfonic acids such as aminoethanesulfonic acid; acidic polysaccharides such as alginic acid; acidic amino acids such as glutamic acid and aspartic acid; and salts of amino acids and inorganic acids such as glycine hydrochloride, aspartic acid hydrochloride, and glutamic acid hydrochloride.
In addition, after one or more selected from these acidic substances are dissolved in water, an appropriate amount of benzamide derivative or a pharmaceutically acceptable salt thereof may be dissolved therein to give an injection solution prepared by a method commonly used by those skilled in the art. At this time, a surfactant such as sodium lauryl sulfate and/or sucrose ester of fatty acid, and/or polyethylene glycol such as polyethylene glycol 4000 and/or polyethylene glycol 6000 may be used together therewith to improve the solubility of the benzamide derivative.
The method of administration of the pharmaceutical preparation of the present invention is not particularly limited, and can be administered by a method suitable for the form of the preparation, the age, sex and severity of symptoms of the patient, and other factors. For example, tablets, pills, liquid drugs, syrups, suspensions, emulsions, granules and capsules are administered orally, while injection solutions are administered intravenously alone or mixed with conventional liquid solutions containing glucose, amino acids and the like; if desired, they may be administered intramuscularly, subcutaneously or intraperitoneally.
The dose of these pharmaceutical preparations of the present invention can be appropriately selected based on the administration method, the age, sex and severity of symptoms of patients, and other factors. However, the dosage of most active ingredients may be about 0.0001-100 mg/day/kg body weight. The amount of active ingredient in a unit dosage form is preferably in the range of about 0.001-1000 mg.
Examples
The present invention will now be described in detail by way of examples and comparative examples. It is to be noted, however, that the present invention is not limited to these examples in any way.
Example 1
100mg of Compound 1 was thoroughly blended with 10ml each of 0.05N hydrochloric acid solution, methanol, ethanol, propylene carbonate, polysorbate 80, polyethylene glycol 400, polyethylene glycol 300, glycerin, dimethylacetamide, or propylene glycol at room temperature, and the supernatant obtained by centrifuging each mixture was separated and used as a drug solution. A control sample for comparison was also prepared by dissolving 100mg of Compound 1 thoroughly with 10ml each of purified water, sodium acetate buffer pH4.0 or sodium phosphate buffer pH6.8 at room temperature and separating the supernatant by centrifugation. Table 2 shows the results of measuring the concentration of compound 1 in each sample by HPLC analysis. All samples of the invention contained compound 1 dissolved at a concentration of 5mg/ml or more, which is sufficient for injection. On the other hand, all of the control samples for comparison contained compound 1 dissolved at a concentration of 0.2mg/ml or less, and thus the concentration necessary for injection could not be secured.
Table 2: solubility comparison of Compound 1 in solvent
| Solvent(s) | Compound 1 concentration (mg/ml) | |
| Control sample for comparison | Sodium acetate hydrateWashing solution, pH4.0 phosphate buffer, pH6.8 | 0.040.20.04 |
| Inventive sample | 0.05N hydrochloric acid solution methanol ethanol propylene carbonate Polysorbate 80 polyethylene glycol 400 polyethylene glycol 300 Glycerol dimethyl acetamide propylene glycol | 14.09.95.417.529.977.769.110.0＞10054.6 |
Example 2
10.13g of polyethylene glycol 400, 1.08g of polysorbate 80 and 200mg of Compound 1 were mixed together and the mixture was thoroughly dissolved by sonication for 30 minutes with occasional mixing. The solution was filled into a hard gelatin capsule so that the dose was 1.5mg/kg based on the body weight of the dog before administration, thereby preparing a pharmaceutical preparation.
Example 3
200mg of Compound 1, 700mg of polyethylene glycol 4000, 800mg of polyethylene glycol 6000, 600mg of sodium lauryl sulfate and 1200mg of sucrose ester of fatty acid were weighed and mixed in an agate mortar, and the mixture was pulverized with a pestle. The mixed powder was filled into a hard gelatin capsule so that the dose was 1.5mg/kg based on the body weight of the dog before administration, thereby preparing a pharmaceutical preparation.
Example 4
200mg of Compound 1, 1350mg of glutamic acid hydrochloride and 1950 mgD-mannitol were weighed and mixed in an agate mortar, and the mixture was pulverized with a pestle. The mixed powder was filled into a hard gelatin capsule so that the dose was 1.5mg/kg based on the body weight of the dog before administration, thereby preparing a pharmaceutical preparation.
Comparative example 1
200mg of Compound 1 and 1000 mgD-mannitol were weighed and mixed in an agate mortar, and the mixture was pulverized with a pestle. The mixed powder was filled into a hard gelatin capsule so that the dose was 1.5mg/kg based on the body weight of the dog before administration, thereby preparing a pharmaceutical preparation.
Example 5
Evaluation test of solubility in Water
Each of the pharmaceutical formulations obtained in examples 2 to 4 and comparative example 1 was mixed with water, and the solubility was evaluated by measuring the concentration of compound 1 by HPLC or observing the transparency and color in the supernatant. Table 3 shows the results of solubility evaluation based on HPLC measurement of the concentration of compound 1 or observation of transparency and color in each supernatant after mixing each formulation (the amount of compound 1 is 20mg) obtained in examples 2 to 4 and comparative example 1 with 1 to 1000ml of purified water. According to the results of example 2, no precipitation of compound 1 was found with mixing with water in any ratio. For examples 3 and 4, the solubility was found to be about 4 times and about 100 times, respectively, that of comparative example 1.
Table 3: solubility of each pharmaceutical preparation in Water
| Amount of water | ||||
| 1ml | 10ml | 250ml | 1000ml | |
| Example 2 example 3 example 4 comparative example 1 | ○××× | ○×○× | ○○○× | ○○○○ |
In the table, the symbol "x" indicates that compound 1 was not dissolved, and the symbol "o" indicates that compound 1 was completely dissolved.
Oral absorbability evaluation test
The pharmaceutical formulations obtained in examples 2 to 4 and comparative example 1 were orally administered to fasted male beagle dogs with a 20ml mouth. Approximately 2.5ml of blood was sampled intravenously into heparinized containers and the blood was centrifuged to collect plasma 15, 30 and 45 minutes and 1, 2, 4, 6 and 9 hours after dosing. The active ingredient was separated from the plasma by solid phase extraction and the concentration was measured by high performance liquid chromatography. The results are shown in FIG. 1. Examples 2-4 all had higher absorbency than comparative example 1.
Table 4 shows the pharmacokinetic parameters of the pharmaceutical formulations obtained in examples 2 to 4 and comparative example 1 to fasted male beagle dogs administered orally with 20ml of water. Examples 2-4 all show higher AUC and Cmax than comparative example 1 with improved absorption by oral administration.
Table 4: pharmacokinetic parameters of the respective pharmaceutical formulations
| Preparation | AUCO 0-∞(μg·hr/ml) | Cmax(μg/ml) | Tmax(hr) |
| Example 2 example 3 example 4 | 0.820.830.92 | 0.850.520.70 | 0.671.080.75 |
| Comparative example 1 | 0.31 | 0.25 | 0.42 |
The values in the table are the average values of n-3.
Industrial applicability
A pharmaceutical preparation and an injection having high oral absorbability, which contain a benzamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient at a high concentration, which can be used as a histone deacetylase inhibitor, are provided by preparing a pharmaceutical solution by dissolving the benzamide derivative or a pharmaceutically acceptable salt thereof in an organic solvent and/or an acidic liquid and preparing a pharmaceutical preparation by adding a surfactant, an acidic substance and/or polyethylene glycol to the benzamide derivative or a pharmaceutically acceptable salt thereof.
Claims (9)
1. A pharmaceutical preparation comprising a benzamide derivative represented by the formula (1):
wherein A represents a structure represented by any one of the following formulae (2):
or a pharmaceutically acceptable salt thereof, and one or more selected from (1) a mixture of polyethylene glycol and a surfactant, (2) a salt of an amino acid and an inorganic acid, and (3) propylene carbonate.
2. The pharmaceutical preparation according to claim 1, wherein the benzamide derivative is represented by the formula (3):
3. the pharmaceutical formulation according to claim 1, wherein the molecular weight of the polyethylene glycol is 200-20,000.
4. The pharmaceutical preparation according to claim 1, wherein the salt of the amino acid and the inorganic acid is one or more selected from glycine hydrochloride, aspartic acid hydrochloride or glutamic acid hydrochloride.
5. The pharmaceutical formulation according to claim 1, wherein the surfactant is one or two selected from the group consisting of an anionic surfactant and a nonionic surfactant.
6. The pharmaceutical formulation according to claim 5, wherein the anionic surfactant is sodium lauryl sulfate.
7. The pharmaceutical preparation according to claim 5, wherein the nonionic surfactant is one or two selected from the group consisting of polyoxyethylene sorbitan fatty acid esters and sugar esters.
8. The pharmaceutical preparation according to claim 7, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.
9. The pharmaceutical formulation according to claim 7, wherein the sugar ester is a sucrose ester of a fatty acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24244499A JP2001081031A (en) | 1999-08-30 | 1999-08-30 | Benzamide derivative-containing preparation having improved solubility and oral adsorption |
| JP242444/99 | 1999-08-30 | ||
| PCT/EP2000/008421 WO2001016106A1 (en) | 1999-08-30 | 2000-08-29 | Benzamide formulation with histone deacetylase inhibitor activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1046277A1 HK1046277A1 (en) | 2003-01-03 |
| HK1046277B true HK1046277B (en) | 2004-11-26 |
Family
ID=17089193
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HK02107642.5A HK1046277B (en) | 1999-08-30 | 2000-08-29 | Benzamide formulation with histone deacetylase inhibitor activity |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US6638530B1 (en) |
| EP (1) | EP1208086B1 (en) |
| JP (2) | JP2001081031A (en) |
| KR (1) | KR100712640B1 (en) |
| CN (1) | CN1147472C (en) |
| AR (1) | AR025434A1 (en) |
| AT (1) | ATE318258T1 (en) |
| AU (1) | AU773617B2 (en) |
| BG (1) | BG65544B1 (en) |
| BR (1) | BR0013648A (en) |
| CA (1) | CA2382886C (en) |
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Effective date: 20110829 |